Mario Mascalchi, Andrea Bianchi, Stefano Ciulli, Andrea Ginestroni, Marco Aiello, Maria Teresa Dotti, Fabrizio Salvi, Emanuele Nicolai, Andrea Soricelli, Stefano Diciotti; Neurol (2017). doi:10.1007/s00415-017-8542-8 DOI: 10.1007/s00415-017-8542-8
Hence ataxia in the disease described by Friedreich may be due to two components: a mal-developmental one affecting spinal cord and medulla and a superimposed degenerative one affecting the cerebellar dentate.
Saturday, June 17, 2017
Friday, June 16, 2017
DNA trinucleotide (GAA) repeats in human genome: hint for disease pathogenesis?
Himanshu Narayan Singh, Barbara Scheiber-Mojdehkar, and Moganty R. Rajeswari, Journal of Biomolecular Structure and Dynamics Vol. 0 , Iss. ja,0 (posted online: 12 Jun 2017) doi:10.1080/07391102.2017.1341336
Short DNA triplet repeats are generally considered to ‘benign’ in nature, however, it can lead to abnormal genetic features by inducing hyper expansion including mutational hotspots, unusual DNA structure etc. Thus, the expanded DNA base triplets in human genome are expected to play crucial role in disease pathogenesis. One such triplet repeat expansion of (GAA) is observed in FXN gene which is well established to cause neurological disease “Friedreich’s ataxia”. Network analyses on disease associated genes were involved with signaling cascade which could be potential target in order to combat disease conditions. Therefore, the genes identified in the present study can throw light on the understanding of role of (GAA) repeats in various disease phenotypes. However, they are required to be further investigated in the in-vitro conditions.
Short DNA triplet repeats are generally considered to ‘benign’ in nature, however, it can lead to abnormal genetic features by inducing hyper expansion including mutational hotspots, unusual DNA structure etc. Thus, the expanded DNA base triplets in human genome are expected to play crucial role in disease pathogenesis. One such triplet repeat expansion of (GAA) is observed in FXN gene which is well established to cause neurological disease “Friedreich’s ataxia”. Network analyses on disease associated genes were involved with signaling cascade which could be potential target in order to combat disease conditions. Therefore, the genes identified in the present study can throw light on the understanding of role of (GAA) repeats in various disease phenotypes. However, they are required to be further investigated in the in-vitro conditions.
Wednesday, June 7, 2017
Neurodegenerative disease mechanism and potential drug identified: Offers hope for patients with Friedreich's Ataxia and related diseases
University of California - Davis. ScienceDaily, 6 June 2017.
Two new studies of neurodegenerative diseases linked to mitochondrial defects offer hope for developing a new biomarker for research and diagnostics, and a drug for treating such diseases.
One of the new studies shows that a loss of the frataxin protein causes a decrease in mitochondrial number in blood and skin cells from patients with Friedreich's ataxia. Mice with a deficiency in the protein also have fewer mitochondria.
In the second study, Cortopassi and colleagues focused on the drug dimethyl fumarate, or DMF, already approved by the FDA for treating adult patients with a relapsing form of multiple sclerosis as well as psoriasis, an autoimmune skin disease.
Two new studies of neurodegenerative diseases linked to mitochondrial defects offer hope for developing a new biomarker for research and diagnostics, and a drug for treating such diseases.
One of the new studies shows that a loss of the frataxin protein causes a decrease in mitochondrial number in blood and skin cells from patients with Friedreich's ataxia. Mice with a deficiency in the protein also have fewer mitochondria.
In the second study, Cortopassi and colleagues focused on the drug dimethyl fumarate, or DMF, already approved by the FDA for treating adult patients with a relapsing form of multiple sclerosis as well as psoriasis, an autoimmune skin disease.
Sunday, June 4, 2017
Tert-butylhydroquinone protects PC12 cells against ferrous sulfate-induced oxidative and inflammatory injury via the Nrf2/ARE pathway
Wenzhe Xu, Feng Li, Zhenkuan Xu, Bin Sun, Jingwei Cao, Yuguang Liu, Chemico-Biological Interactions, Available online 2 June 2017, ISSN 0009-2797, doi:10.1016/j.cbi.2017.05.021
Increasing evidence had proved the critical role of iron in the pathogenesis of numerous neurodegenerative diseases because of its capacity to promote the formation of reactive oxygen species (ROS). Tert-butylhydroquinone (tBHQ) was a metabolite of butylated hydroxyanisole, a widely used food antioxidant. tBHQ could change the conformation of the Keap1-Nrf2 complex and helps Nrf2 escape from Keap1-mediated degradation, which can lead to Nrf2 stabilization. tBHQ has been proven to exert neuroprotective effects in different models of CNS injury and has been approved for human use
Free iron exhibits cytotoxicity because of its ability to promote the generation of reactive oxygen species (ROS), which could lead to lipid peroxidation, DNA strand breaks, degradation of biomolecules, and induce inflammatory response. Brain iron content tends to increase during healthy aging, while excessive iron deposits are found in neuritic plaques in brains with Alzheimer’s disease, substantia nigra in Parkinson’s disease, basal ganglia in Huntington’s disease and dorsal root ganglia in Friedreich’s ataxia (FRDA). This study proved the beneficial effects of tBHQ on the attenuation of iron-induced neurotoxicity, suggesting the therapeutic potential of tBHQ for neurodegenerative diseases.
Increasing evidence had proved the critical role of iron in the pathogenesis of numerous neurodegenerative diseases because of its capacity to promote the formation of reactive oxygen species (ROS). Tert-butylhydroquinone (tBHQ) was a metabolite of butylated hydroxyanisole, a widely used food antioxidant. tBHQ could change the conformation of the Keap1-Nrf2 complex and helps Nrf2 escape from Keap1-mediated degradation, which can lead to Nrf2 stabilization. tBHQ has been proven to exert neuroprotective effects in different models of CNS injury and has been approved for human use
Free iron exhibits cytotoxicity because of its ability to promote the generation of reactive oxygen species (ROS), which could lead to lipid peroxidation, DNA strand breaks, degradation of biomolecules, and induce inflammatory response. Brain iron content tends to increase during healthy aging, while excessive iron deposits are found in neuritic plaques in brains with Alzheimer’s disease, substantia nigra in Parkinson’s disease, basal ganglia in Huntington’s disease and dorsal root ganglia in Friedreich’s ataxia (FRDA). This study proved the beneficial effects of tBHQ on the attenuation of iron-induced neurotoxicity, suggesting the therapeutic potential of tBHQ for neurodegenerative diseases.
Friday, June 2, 2017
Is Reata's Friedreich's Ataxia Study a Failure?
Rare Disease ReportData from a Phase 2 Friedreich’s ataxia (FA) study by Reata Pharmaceuticals is making its rounds on social media today. The data, according to Reata, is exceptional. However, according to many on Twitter, the trial is a failure.
In spite of what the critics think, the company and the advocacy group Friedreich’s Ataxia Research Alliance (FARA) are cautiously optimistic.
About: Rare Disease Report is a website and weekly e-newsletter that offers an independent voice for the Rare Disease Community. It strives to bring together medical, scientific, investment, regulatory, and advocate professionals interested in rare diseases and orphan drugs.
NOTE: This is a news published on the web, from a news source that is usually rigorous. I usually try to publish here all the scientific news around the FA, without censorship. This means that I do not always necessary should agree with the opinions.
In spite of what the critics think, the company and the advocacy group Friedreich’s Ataxia Research Alliance (FARA) are cautiously optimistic.
About: Rare Disease Report is a website and weekly e-newsletter that offers an independent voice for the Rare Disease Community. It strives to bring together medical, scientific, investment, regulatory, and advocate professionals interested in rare diseases and orphan drugs.
NOTE: This is a news published on the web, from a news source that is usually rigorous. I usually try to publish here all the scientific news around the FA, without censorship. This means that I do not always necessary should agree with the opinions.
Reata Pharmaceuticals, Inc. Announces Positive Data From Part One of Moxie Trial of Omaveloxolone for Friedreich’s Ataxia
IRVING, Texas, June 01, 2017 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq:RETA) (“Reata” or “the Company”), a clinical-stage biopharmaceutical company, today announced positive data from Part 1 of the Company’s Phase 2 trial (MOXIe) of omaveloxolone for the treatment of Friedreich’s ataxia (FA). The trial demonstrated that in FA patients, omaveloxolone induced Nrf2, which is suppressed in FA patients, and this was associated with improvements in mitochondrial and neurological function. Dose-dependent and time-dependent effects on the modified Friedreich’s Ataxia Rating Scale (mFARS) were observed at the pharmacodynamically active doses, and the maximum effect on mFARS was observed at the 160 mg dose level. The Company is planning to initiate Part 2 of MOXIe during the second half of 2017.
Friedreich’s ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency
Duncan E. Crombie, Claire L. Curl, Antonia JA Raaijmakers, Priyadharshini Sivakumaran, Tejal Kulkarni, Raymond CB Wong, Itsunari Minami, Marguerite V. Evans-Galea, Shiang Y. Lim, Lea Delbridge, Louise A. Corben, Mirella Dottori, Norio Nakatsuji, Ian A. Trounce, Alex W. Hewitt, Martin B. Delatycki, Martin F. Pera, Alice Pébay; Aging (Albany NY). 2017; 9:1440-1452. doi: 10.18632/aging.101247.
FRDA- cardiomyocytes display a significant increase in beat rate variability, demonstrating a potential for cardiac dysfunction, compared to the control cardiomyocytes. These data also suggest that impairment in Ca2+ handling is responsible for the observed electrophysiological phenotype. This was confirmed by assessing Ca2+ transients. In the FRDA-cardiomyocytes significantly lower diastolic and systolic Ca2+ levels and reduced transient amplitude signals were observed compared with control cardiomyocytes. Collectively, our data demonstrates a Ca2+ handling impairment in the FRDA cardiomyocytes.
FRDA- cardiomyocytes display a significant increase in beat rate variability, demonstrating a potential for cardiac dysfunction, compared to the control cardiomyocytes. These data also suggest that impairment in Ca2+ handling is responsible for the observed electrophysiological phenotype. This was confirmed by assessing Ca2+ transients. In the FRDA-cardiomyocytes significantly lower diastolic and systolic Ca2+ levels and reduced transient amplitude signals were observed compared with control cardiomyocytes. Collectively, our data demonstrates a Ca2+ handling impairment in the FRDA cardiomyocytes.
Thursday, June 1, 2017
Single-step blood direct PCR: A robust and rapid method to diagnose triplet repeat disorders
Inder Singh, Vishnu Swarup, Sunil Shakya, Vinay Goyal, Mohammed Faruq, Achal Kumar Srivastava, Single-step blood direct PCR: A robust and rapid method to diagnose triplet repeat disorders, Journal of the Neurological Sciences, Available online 22 May 2017, ISSN 0022-510X, doi:10.1016/j.jns.2017.05.042.
The nearly-accurate sizing of the normal and expanded allele was achieved in a shorter time (4–5 h), without DNA extraction and any risk of cross contamination, which suggests the BD-PCR to be a reliable, inexpensive, and rapid method to confirm TRDs. This technique can be introduced in routine diagnostic procedures of other tandem repeat disorders.
The nearly-accurate sizing of the normal and expanded allele was achieved in a shorter time (4–5 h), without DNA extraction and any risk of cross contamination, which suggests the BD-PCR to be a reliable, inexpensive, and rapid method to confirm TRDs. This technique can be introduced in routine diagnostic procedures of other tandem repeat disorders.
Wednesday, May 31, 2017
Developing gene and cell therapies for rare diseases: an opportunity for synergy between academia and industry
F Mavilio; Gene Therapy , (25 May 2017) doi:10.1038/gt.2017.36
For the last 20 years, academic research has been the major, and often only, driving force behind the spectacular development of gene transfer technology for the therapy of rare genetic diseases. Investors and industry became eventually interested in gene and cell therapy, due to the success of a series of pioneering clinical trials that proved efficacy and safety of last-generation technology, and to favorable orphan drug legislation in both Europe and the United States. Developing this forms of therapy is however complex and requires skills and knowledge not necessary available to the industry, which is better placed to develop processes and products and put them on the market. Cooperation between academia and industry is an opportunity to de-risk innovative approaches and ensure a faster and more economical development of therapies for diseases with high unmet medical needs and low-profit expectations.
For the last 20 years, academic research has been the major, and often only, driving force behind the spectacular development of gene transfer technology for the therapy of rare genetic diseases. Investors and industry became eventually interested in gene and cell therapy, due to the success of a series of pioneering clinical trials that proved efficacy and safety of last-generation technology, and to favorable orphan drug legislation in both Europe and the United States. Developing this forms of therapy is however complex and requires skills and knowledge not necessary available to the industry, which is better placed to develop processes and products and put them on the market. Cooperation between academia and industry is an opportunity to de-risk innovative approaches and ensure a faster and more economical development of therapies for diseases with high unmet medical needs and low-profit expectations.
Tuesday, May 30, 2017
Blood–brain barrier peptide shuttles
Macarena Sánchez-Navarro, Ernest Giralt, Meritxell Teixidó, Current Opinion in Chemical Biology, Volume 38, June 2017, Pages 134-140, ISSN 1367-5931, doi:10.1016/j.cbpa.2017.04.019.
Brain delivery is hampered by the presence of the blood–brain barrier (BBB), a natural defence of the brain that protects it and allows the entrance of nutrients by several mechanisms. Taking advantage of these mechanisms is an opportunity to treat brain related diseases. Among the different alternatives, BBB peptide shuttles are gaining attention to increase brain delivery of therapeutics.
Peptides shuttles present several advantages over the brain delivery system alternatives. For instance, peptides are amenable for chemical synthesis, and present low toxicity. Some of the challenges of its application are already being solved. The recent development of new and more efficient BBB-shuttles will lead to more pre- clinical studies, and hopefully, to clinical evaluations in the following years.
Brain delivery is hampered by the presence of the blood–brain barrier (BBB), a natural defence of the brain that protects it and allows the entrance of nutrients by several mechanisms. Taking advantage of these mechanisms is an opportunity to treat brain related diseases. Among the different alternatives, BBB peptide shuttles are gaining attention to increase brain delivery of therapeutics.
Peptides shuttles present several advantages over the brain delivery system alternatives. For instance, peptides are amenable for chemical synthesis, and present low toxicity. Some of the challenges of its application are already being solved. The recent development of new and more efficient BBB-shuttles will lead to more pre- clinical studies, and hopefully, to clinical evaluations in the following years.
Subscribe to:
Posts (Atom)
